Regulation of SLCO4C1 transporter-mediated excretion of uremic toxins as a therapeutic strategy for Chronic Kidney Disease

• Project/Area Number: 24890013
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: Tohoku University
• Principal Investigator: AKIYAMA Yasutoshi 東北大学, 東北メディカル・メガバンク機構, 非常勤講師 (70635557)
• Project Period (FY): 2012-08-31 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: トランスポーター / 尿毒症 / 尿毒素 / 慢性腎臓病 / SLCO4C1 / インドキシル硫酸 / 尿毒症物質

Research Abstract

Chronic kidney disease (CKD) is a global health problem that carries a substantial risk for cardiovascular morbidity and death. With the progression of CKD, various uremic toxins accumulate, subsequently causing renal damage and hypertension. Recently, we have revealed that kidney-specific organic anion transporter SLCO4C1 excretes uremic toxins, and the up-regulation of SLCO4C1 resulted in the reduction of blood pressure and renal inflammation in a CKD model. In this study, we revealed that indoxyl sulfate (IS), one of the best-known uremic toxins, inhibits the expression of SLCO4C1 through GATA3 and that removal of IS increases the SLCO4C1 expression. The combination therapy of, (1) activating the SLCO4C1 expression by statins, (2) reducing the plasma IS concentration by the administration of AST-120 and (3) administering GATA inhibitor, could be a more effective remedy for the excretion of uremic toxins and preservation of renal function in CKD patients.

Research Products

• [Journal Article] Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regul ation of GATA3 (2013)
  • Author(s): Akiyama Y, Kikuchi K, Saigusa D, Suzuki T, Takeuchi Y, Mishima E, Yamamoto Y, Ishida A, Sugawara D, Jinno D, Shima H, Toyohara T, Suzuki C, Souma T, Moriguchi T, Tomioka Y, Ito S, Abe T.
  • Journal Title: PLoS One Volume: 8 Issue: 7 Pages: e66518-e66518
  • DOI: 10.1371/journal.pone.0066518
  • Peer Reviewed
• [Journal Article] 尿毒素の輸送とCKD (2013)
  • Author(s): 2.秋山泰利、阿部高明
  • Journal Title: 腎と骨代謝 Volume: 26 Pages: 223-229
• [Journal Article] A metabolomic approach to clarifying the effect of AST-120 on 5/6 nephrectomized rats by capillary electrophoresis with mass spectrometry (CE-MS). (2012)
  • Author(s): Akiyama Y.
  • Journal Title: Toxins Volume: 4 Issue: 11 Pages: 1309-1322
  • DOI: 10.3390/toxins4111309
  • Peer Reviewed
• [Journal Article] Carrier-mediated transport of quercetin conjugates : Involvement of organic anion transporters and organic anion transporting polypeptides (2012)
  • Author(s): Wong C, Akiyama Y, Abe T et al.
  • Journal Title: Biochem. Pharmacol Volume: 84 Issue: 4 Pages: 564-570
  • DOI: 10.1016/j.bcp.2012.05.011
  • Peer Reviewed
• [Presentation] Indole-3-acetate Inhibits Erythropoietin Receptor Expression and Erythropoietin Signaling in vitro (2013)
  • Author(s): 秋山 泰利
  • Organizer: アメリカ腎臓学会
  • Place of Presentation: アメリカ アトランタ
• [Presentation] A metabolomic approach to clarifying the effect of AST-120 on 5/6 nephrectomized rats by capillary electrophoresis with mass spectrometry (CE-MS) (2012)
  • Author(s): 秋山泰利
  • Place of Presentation: アメリカ腎臓学会
• [Presentation] Metabolomic approach for clarifying the effect of AST-120 in 5/6 nephrectomized rats by capillary electrophoresis mass spectrometry (2012)
  • Author(s): 秋山 泰利
  • Organizer: アメリカ腎臓学会
  • Place of Presentation: アメリカ サンディエゴ
• [Book] 慢性腎不全の病態トピックス9トランスポーター, 腎不全治療レシピ, 査読なし (2013)
  • Author(s): 秋山泰利、阿部高明
  • Publisher: 医学出版
• [Book] Annual Review腎臓 (2013)
  • Author(s): 秋山 泰利
  • Total Pages: 9
  • Publisher: 中外医学社